Tumor therapy with antiangiogenic beta-2-glycoprotein 1

使用抗血管生成 β-2-糖蛋白 1 进行肿瘤治疗

• 批准号: 6827241
• 负责人: ALAN Jay SCHROIT
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827241
• 关键词: SDS polyacrylamide gel electrophoresis; affinity chromatography; angiogenesis inhibitors; blood proteins; clinical research; enzyme linked immunosorbent assay; flow cytometry; fluorescence microscopy; glycoproteins; green fluorescent proteins; growth inhibitors; high performance liquid chromatography; human tissue; ion exchange chromatography; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer therapy; neoplastic growth; polymerase chain reaction; protein purification; protein structure function; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): Several negative regulators of angiogenesis are the same proteins that control the formation and dissolution of fibrin clots during wound healing. These include coagulation proteins antithrombin III, prothrombin and fibrinogen and their proteolytic fragments, prothrombin fragments-1 and -2 and angiostatin. Beta-2-glycoprotein 1 (beta2GBP1), a 50 kDa plasma protein, regulates thrombosis by competing for the assembly of coagulation factors. Using a subcutaneous implant comprised of gelatin and agarose that accurately quantifies the formation of new blood vessels, we observed that embedded beta2GBP1 completely blocked the invasion of new blood vessels into the implant suggesting that it could inhibit tumor angiogenesis. Therapy studies using the B16 melanoma, UV2237 flbrosarcoma and TRAMP prostate carcinoma mouse tumor models showed that repeated administration of the protein significantly inhibited the growth of all the tumors studied and lung metastasis in the B16 melanoma model. In vitro studies showed that beta2GBP1 specifically inhibited endothelial cell growth, cord formation and cell migration, suggesting that inhibition of tumor growth might be due to inhibition of angiogenesis. Studies on the effects of the protein on normal vasculature in vivo, on the other hand, showed complete inhibition of growth factor-induced, but not chemically-induced blood vessel dilatation suggesting that inhibition of tumor growth occurred via an angioectasia-dependent mechanism. In this proposal, we will examine the mechanism of beta2GBP1-dependent inhibition of tumor cell growth and its potential as a new therapeutic modality for the treatment of cancer.

描述（由申请人提供）：血管生成的几个负调节剂是控制纤维蛋白血块在伤口愈合过程中的形成和溶解的相同蛋白质。这些包括凝血蛋白抗凝血酶III，凝血酶原和纤维蛋白原及其蛋白水解片段，凝血酶原片段-1和-2和Angiostatin。 β-2-糖蛋白1（BetA2GBP1），一种50 kDa等离子体蛋白，通过竞争凝结因子的组装来调节血栓形成。我们使用由明胶和琼脂糖组成的皮下植入物准确地量化了新血管的形成，我们观察到嵌入的beta2gbp1完全阻止了将新血管侵袭到植入物中，这表明它可以抑制肿瘤血管生成。使用B16黑色素瘤，UV2237 Flbrosarcoma和Tramp Prostate癌小鼠肿瘤模型的治疗研究表明，重复给药蛋白质会显着抑制B16黑色素瘤模型中所有研究的肿瘤和肺转移的生长。体外研究表明，Beta2GBP1特别抑制 内皮细胞生长，绳索形成和细胞迁移，表明抑制肿瘤生长可能是由于抑制了血管生成。另一方面，对蛋白质对体内正常血管的作用的研究表明，对生长因子诱导的完全抑制作用，但没有化学诱导的血管扩张，这表明抑制肿瘤生长是通过血管息张依赖性机制发生的。在此提案中，我们将研究BetA2GBP1依赖性抑制肿瘤细胞生长的机制及其作为治疗癌症的新治疗方式的潜力。